United States (US) soldiers who have served in Iraq show an increased risk for allergic rhinitis and asthma; soldiers deployed in the Persian Gulf had twice the risk of developing allergic rhinitis as compared to homeland stationed personnel and 1.6 times the risk of developing asthma. Furthermore, the diagnosis of asthma with symptoms after the age of 12 years is an exclusion criterion for military enlistment. While the rea- son for the increased risk for allergic inflammatory diseases has not been established, exposure to high levels of dust and other inhaled particles is thought to be the most likely explanation. The ubiquitous environmental allergen, house dust mite (HDM), was found in high levels in the tents of soldiers serving in Iraq and is known to be a major inducer of asthma. It has been estimated that between 50-80% of rhinitis and asthma is due to HDM. However, the mechanisms by which HDM induces and exacerbates asthma are not fully understood. HDM and many other inhaled particulates contain stimulatory structures we have termed allergen-as- sociated molecular patterns (AAMPs) that engage and stimulate innate pattern recognition receptors (PRR). While others have studied the effects of HDM on epithelial and dendritic cells, we have found that HDM directly activates the macrophage (M?) - a cell that is central in the innate immune system and found in abundance in the lungs and airways. HDM stimulates M?s to induce the expression of IFN? and several genes that are char- acteristic of alternatively-activated M?s (also termed M2 M?s), including chitinase family members. We identi- fied a novel pathway between the induction of IFN? and caspase 11 that controls chitinase gene expression and M? morphology without inducing high levels of IL-1? or pyroptosis. Furthermore, our preliminary data show that: (i) HDM stimulates an increase in caspase 11 protein and enzyme activity in a TLR4-independent manner; (ii) caspase 11 is required for chitinase gene expression and optimal IFN? induced by HDM in vitro; (iii) HDM induces a dramatic change in M? size and shape with pronounced changes in actin dynamics, {a response replicated by dust samples from Camp Victory, Iraq; (iv) HDM stimulates expression of protein spe- cies indicative of autophagy-related processes, such as LC-3 lipidation, without degradative flux;} and (v) we observed similar HDM-induced changes in human primary M?s. Thus, our overall goal in this renewal proposal is to characterize the mechanism by which the non-canonical caspase 11 pathway controls M? phenotype and thus HDM-induced asthma. An understanding of this process is clinically important since human asthmatics have elevated numbers of M2, as well as increased amounts of chitinase proteins in their blood and airways- especially during asthma exacerbations. Furthermore, we have shown that M2 initiate and amplify the symp- toms of asthma in a mouse model. The central hypothesis to be tested is that the caspase 11 pathway regulates the expression of a sub- set of M2 genes in M?s and controls M? morphology and migration by regulating actin dynamics critical for phagolysome and autophagosome fusion, thereby enhancing allergy and asthma. The specific aims designed to test this hypothesis are: 1) to characterize the role of caspase 11 in regulating HDM-induced changes in M? phenotype and allergic lung inflammation, 2) to delineate the contribution of caspase 11 and autophagic ma- chinery to the regulation of actin dynamics and M? motility induced by HDM, and 3) to validate HDM-induced responses in human M?s and {compare responses in M?s from from asthmatics and control subjects.} The anticipated outcome of our research is that it will delineate the signaling pathways activated by the ubiquitous environmental allergen HDM that drive expression of M2 genes and M? function. This increase in knowledge will have benefit for Veterans and the nation because these pathways will likely lead to the identifi- cation of new targets for the control of HDM-induced allergic rhinitis and asthma.